Common Industrial Chemicals In Tiny Doses Raise
Health Issue
Advanced Tests Often Detect Subtle Biological Effects;
Are Standards Too Lax?
Getting in Way of Hormones
PETER WALDMAN / Wall Street Journal 25jul2005
Levels of Risk
For years, scientists have struggled to explain rising rates of some cancers and childhood
brain disorders. Something about modern living has driven a steady rise of certain
maladies, from breast and prostate cancer to autism and learning disabilities.
One suspect now is drawing intense scrutiny: the prevalence in the environment of
certain industrial chemicals at extremely low levels. A growing body of animal research
suggests to some scientists that even minute traces of some chemicals, always assumed to
be biologically insignificant, can affect such processes as gene activation and the brain
development of newborns.
An especially striking finding: It appears that some substances may have effects at the
very lowest exposures that are absent at higher levels.
Some scientists, many of them in industry, dismiss such concerns. But the new science of
low-dose exposure is challenging centuries of accepted wisdom about toxic substances
and rattling the foundation of environmental law.
Modern pollution restrictions aim to limit exposures to levels past studies have found
safe. For example, it's known mercury can cause learning problems in children if it's
above 58 parts per billion in the bloodstream. Dividing 58 by 10 to provide a margin of
safety, U.S. regulators advise that children and young women not accumulate more than
5.8 parts per billion of mercury, by limiting consumption of certain fish such as tuna.
But what if it turned out some common substances have essentially no safe exposure
levels at all? That was ultimately what the U.S. Environmental Protection Agency
concluded about lead after studying its effects on children for decades. Indications some
other chemicals may have no safe limits have led regulators in Europe and Japan to bar
the use of certain compounds in toys and in objects used to serve food. In the U.S.,
federal scientists are devising new tests that could be used to screen thousands of
common chemicals to make sure they're safe at extremely low exposures.
Using advanced lab techniques, scientists have found that with some chemicals, traces as
minute as mere parts per trillion have biological effects. That's one-millionth of the
smallest traces even measurable three decades ago, when many of today's environmental
laws were written. With some of these chemicals, such trace levels exist in the blood and
urine of the general population.
Some chemical traces appear to have greater effects in combination than singly, another
challenge to traditional toxicology, which tests things individually.
EXPOSURE MILESTONES
Research findings on the effects of bisphenol A (BPA)
contrasted with EPA guidelines
Daily dose in milligrams per kilogram of body weight.
1988 0.05 mg EPA's predicted safe dose for humans
1997 0.002 mg Linked to enlarged prostate in male mice
1999 0.0024 mg Linked to early puberty in female mice
2003 0.0002 mg Linked to altered sperm in male rats
Relative Size Comparison
Scientists have found effects on rodents from steadily
smaller exposures to some chemicals, such as Bisphenol A,
used in food-can linings and polycarbonate plastic.
Source: scientific articles.
The human body is complex, and effects seen in tests on small laboratory animals and in
human cells don't necessarily mean health risks to people. "The question is what do we
do about these low levels once we know they're there," says Steve Hentges of the
American Plastics Council, a trade association.
For their part, companies and industry groups have attacked low-dose research as
alarmist and are challenging the findings with scientific studies of their own. Some
industry studies have contradicted the low-dose findings of university and government
labs. One reason, says Rochelle Tyl, a toxicologist who does rodent studies on contract
for industry groups, is that academics seek "to find out if a chemical has an intrinsic
capacity to do harm," while industry scientists try to measure actual dangers to people.
The result is that low-dose research has sparked a number of heated scientific and
regulatory controversies:
 Tiny doses of bisphenol A, which is used in polycarbonate plastic baby bottles
and in resins that line food cans, have been found to alter brain structure,
neurochemistry, behavior, reproduction and immune response in animals. Makers



and users of the chemical maintain, citing a Harvard review of 19 studies, that the
chemical is harmless to humans at such levels. (See illustration above)
Minute levels of phthalates, which are used in toys, building materials, drug
capsules, cosmetics and perfumes, have been statistically linked to sperm damage
in men and genital changes, asthma and allergies in children. The U.S. Centers for
Disease Control and Prevention has detected comparable levels in Americans'
urine. Manufacturers say there is no reliable evidence that phthalates cause any
health problems.
A chemical used in munitions, called perchlorate, is known to inhibit production
of thyroid hormone, which children need for brain development. The chemical
has been detected in drinking-water supplies in 35 states, as well as in fruits,
vegetables and breast milk. The EPA has spent years mulling what is a safe level
in drinking water. The Defense Department and weapons makers maintain it is
harmless at much higher doses than those that Americans ingest.
The weed killer atrazine has been linked to sexual malformations in frogs that
were exposed to water containing just 1/30th as much atrazine as the EPA regards
as safe in human drinking water. The herbicide's main manufacturer, Syngenta
AG, says other studies prove atrazine is safe. The EPA favors more study.
In The Laboratory
Studies have linked some common chemicals
with toxic effect, though not necessarily at
levels to which humans are exposed:
What's it
Chemical What's it in
linked to
----------------------------------------------------Bisphenol A Polycarbonate
Altered brain,
(BPA)
plastic bottles
behavior and sex
and food-can
linings
----------------------------------------------------Dibutyl
Cosmetics
Gene and hormone
Phthalate
shampoos, pills
changes in rodents;
(DBP)
nail polish,
genital abnormalities
plastic toys
in human infants
----------------------------------------------------Diethylhexy Polyvinylchloride Birth defects in
Phthalate
building products, mice; pre-term birth
(DEHP)
food packaging,
in human infants;
toys, medical
early puberty in girls
tubing
----------------------------------------------------Perchlorate Drinking water in
Brain and behavior
35 states, fruits,
changes in rats;
vegetables,
thyroid effects in
breast milk
people
----------------------------------------------------sources: Scientific articles; US Environmental Protection Agency
With so much still unknown, regulators are proceeding on different tracks in different
countries. Japan's government designates about 70 chemicals as potential "endocrine
disruptors" — substances that may, at tiny doses, interfere with hormonal signals that
regulate human organ development, metabolism and other functions. Japan has just
completed a $135 million research push on endocrine disruptors, including setting up a
national research center. The Japanese government also has banned certain phthalates in
food handlers' gloves and containers, after detecting them in food. One manufacturer,
Fujitsu Ltd., has pledged to phase out its use of most suspected endocrine disruptors over
coming years.
The European Union has banned some kinds of phthalates in cosmetics and toys, and it is
considering a ban on nearly all phthalates in household goods and medical devices. The
EU also is planning to require new safety tests for thousands of industrial chemicals,
many of which already exist in people's bodies at trace levels. Industry, which would
have to bear the cost of proving countless current products safe, is fighting the measures,
calling them a massive unnecessary burden.
In the U.S., there are divisions within the government. The White House plays down the
issue, saying the low-dose hypothesis is unproved. But many federal scientists and
regulators at the EPA and Health and Human Services Department are forging ahead with
new methods for assessing possible low-dose dangers. Legislatures in two states,
California and New York, are considering bills that would ban use of certain phthalates in
toys, child-care products and cosmetics, while a California bill would restrict bisphenol
A.
Earliest Concerns
One of the early scientists to focus on possible low-dose risks was biologist Theo
Colborn of the World Wildlife Fund. Studying the decline of certain birds, mammals and
fish in the upper Midwest, Dr. Colborn spotted some patterns: Species that struggled to
survive in the industrialized Great Lakes thrived in inland areas that were less polluted.
And some offspring in more-polluted regions had gender abnormalities, such as
feminized sex organs in males. She theorized that trace amounts of chemicals in the
environment were disrupting hormones.
Dr. Colborn and colleagues popularized low-dose concerns in a series of conferences,
articles and a best-selling 1996 book called "Our Stolen Future." That year the EPA
asked an outside advisory panel to consider ways of screening industrial chemicals for
hormonal effects, a process still incomplete.
In 2000, a separate EPA-organized panel, after reviewing 49 studies, said some
hormonally active chemicals affect animals at doses as low as the "background levels" to
which the general human population is subject. The panel said the health implications
weren't clear but urged the EPA to revisit its regulatory procedures to make sure such
chemicals are tested in animals at appropriately small doses.
The EPA hesitated. It responded in 2002 that "until there is an improved scientific
understanding of the low-dose hypothesis, EPA believes that it would be premature to
require routine testing of substances for low-dose effects."
The Bush administration's regulatory czar, John Graham — administrator of the Office of
Information and Regulatory Affairs at the White House Office of Management and
Budget — later publicly dismissed as unproven the idea that the hormonal system could
be disrupted by multiple low-dose exposures to industrial chemicals. For the past two
years, the administration has proposed funding cuts for EPA research on suspected
endocrine disrupters, but Congress has kept the funding roughly level at about $10
million a year.
Since the review panel met in 2000, scientists have published more than 100 peerreviewed articles reporting further low-dose effects in living animals and in human cells.
These findings are generating some early insights in the thorny process of translating
laboratory data into conclusions about human health.
Less Is More
One of the most provocative is that some hormonally active chemicals seem to have more
effects at extremely low exposures than at higher ones. This challenges an axiom of
toxicology stated by the Swiss chemist Paracelsus nearly 500 years ago: The dose makes
the poison.
Toxicologists traditionally derive risk by exposing rodents to chemicals to find the lowest
dose that leads to tumors, birth defects or other readily observable effects. Regulators
then divide the highest "no-observable-effect" dose by an "uncertainty factor" —
anywhere from 10 to 1,000 — to set a maximum human exposure they can be confident
is safe.
But now researchers have found chemicals that have hormonal effects on lab animals and
on human cells in much tinier amounts than their standard no-observable-effect levels.
And with some of these chemicals, as the tiny doses given to animals are increased, the
effects recede. Then, at much higher levels, broad systemic impacts appear, such as
reduced body weight.
An example is bisphenol A, or BPA, the ingredient in polycarbonate baby bottles and
food-can linings. It evidently is widespread in the environment. In the U.S., the CDC has
found traces of it in 95% of urine samples tested. In Japan, researchers have detected
BPA in fetal amniotic fluid and the umbilical cords of newborns.
Studying BPA in rats in 1988, the EPA concluded the lowest exposure with an "observed
adverse effect" was 50 milligrams a day per kilogram of body weight (one kilogram = 2.2
pounds). Dividing 50 by an uncertainty factor of 1,000, the agency set a daily safe limit
for humans of 0.05 milligrams of BPA per kilogram of body weight. Since then,
however, academic scientists in several countries have done more than 90 studies that
have found BPA effects on animals and human cell cultures from exposures well below
this level.
The EPA used a relatively crude measure of the chemical's effects: changes in rodents'
body weights. The new studies looked at subtler, hormone-related effects. Some studies
found changes in rodents' reproductive organs and brains at doses as low as 0.002
milligram per kilogram of body weight per day. That is just one-25,000th the dose that
the EPA said was the lowest exposure having an observable adverse effect.
Disrupting Hormones
Seeking to explain this pattern, scientists cite the endocrine system's exquisite sensitivity.
Animals and humans secrete infinitesimal amounts of various hormones, such as
estrogen, that trigger responses when they occupy special receptors on the cells of various
organs. BPA is among numerous chemicals that can mimic estrogen by occupying cells'
estrogen receptors. When they do this at critical phases of development, the chemicals
can trigger unnatural biological responses, such as brain and reproductive abnormalities.
At higher doses, however, BPA and other endocrine disruptors — instead of triggering
the unnatural responses — appear to overwhelm the receptors. That explains, scientists
say, why some chemicals seem to have more potent hormonal effects at very low doses
than at higher ones.
Mr. Hentges of the American Plastics Council says studies show BPA is harmless at the
tiny levels to which humans are exposed. In 2001 the plastics council agreed to pay
Harvard's Center for Risk Analysis, part of the Harvard School of Public Health,
$600,000 to review BPA studies. The 10 panelists found "no consistent affirmative
evidence of low-dose BPA effects" on the basis of 19 studies that were selected by April
2002 for review.
However, many more BPA studies kept coming out, and when the center published its
report last fall, three of the 10 panelists declined to be listed as authors. "There are other
papers published after the 'cut-off' date that the panel did not review that may have
altered their conclusions," says one of the three, Paul Foster of the National Institute of
Environmental Health Sciences. A fourth, Claude Hughes of Quintiles Transnational
Corp., a pharmaceutical consulting firm, signed but made the same point in a journal
commentary criticizing the report and calling for a new EPA risk assessment. The
Harvard risk center's executive director, George Gray, acknowledges that a "torrent of
new papers on BPA" may have made it impossible for the panel to review everything by
its deadline.
The plastics council's Mr. Hentges says his group reviews all studies on BPA and
believes none have changed the basic conclusion of the Harvard report. "We continue to
believe that the weight of evidence indicates BPA poses no risk to human health," he
says.
Chemicals in Combination
Environmental chemicals don't exist in isolation. People are exposed to many different
ones in trace amounts. So scientists at the University of London checked a mixture. They
tested the hormonal strength of a blend of 11 common chemicals that can mimic
estrogen.
Alone, each was very weak. But when scientists mixed low doses of all 11 in a solution
with natural estrogen — thus simulating the chemical cocktail that's inside the human
body today — they found the hormonal strength of natural estrogen was doubled. Such
an effect inside the body could disrupt hormonal action.
"In isolation, the contribution of individual [estrogen-like chemicals] at the
concentrations found in wildlife and human tissues will always be small," wrote the
scientists, led by Andreas Kortenkamp, who directs research on endocrine disruptors for
the EU. But because such compounds are so widespread in the environment, the
researchers concluded, the cumulative effect on the human endocrine system is "likely to
be very large."
To test chemicals, toxicologists traditionally dose animals with a single substance and
then dissect them. But this method can't spot the subtle effects associated with today's
multiple exposures to low-dose chemicals, says John Bucher, of the National Institute of
Environmental Health Sciences.
Now he and his boss, Christopher Portier, are revamping the federal government's
National Toxicology Program, which sets standards for how chemicals are tested. Over
about seven years, they hope to develop a series of lab tests that will ultimately screen
some 100,000 industrial compounds, individually and in mixtures, for biochemical
"markers" such as effects on specific genes.
The chemicals then will be ranked by mechanism of action and suspected toxicity, and
assigned priorities for further study. "It's taken us 25 years and $2 billion to study 900
chemicals," Dr. Portier says. "If this works, we can study 15,000 in a year."
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